Abstract Hookah (water-pipe) smoking is rapidly increasing in popularity worldwide. Contributing to this popularity is the unsubstantiated belief that traditional hookah smoke is detoxified as it passes through the water-pipe. More recently, electronic hookah bowls?containing e-liquid that is heated electrically but inhaled through traditional water-pipes?are increasing in popularity in the United States among young female adults, who endorse marketing claims that these products are even safer than traditional hookah. With traditional hookah, in addition to nicotine and tar, smokers are exposed to carbon-enriched fine particles and significant amounts of carbon monoxide (CO), the latter of which has been shown to constitute an endothelial-dependent vasodilator. Though toxicant exposure is much lower than traditional hookah and without any CO exposure, e-hookah bowls deliver nicotine and fine particles that constitute putative vascular toxins. The main objective of this project is to investigate the comparative effects of traditional hookah smoking versus electronic hookah bowl inhalation on endothelial and vascular function and their mechanistic role in the development of cardiovascular disease. Specifically, we will examine the role of oxidative stress and inflammation as potential mechanisms of action in hookah-induced cardiovascular disease. We will test the hypothesis that; 1) in the absence of charcoal briquettes and virtually any CO exposure, e-hookah bowl inhalation acutely impairs endothelial function and evokes acute central stiffness, opposite from the endothelial function augmentation observed after traditional hookah smoking, which is likely mediated by the large CO boost emitted from burning charcoal briquettes used to heat the flavored tobacco; and 2) the processes of oxidative stress and inflammation play a pivotal mechanistic role underlying these vascular changes. In a cross-over study comparing traditional hookah smoking to e-hookah bowl inhalation, we will assess endothelial function measured by brachial artery flow- mediated dilation and aortic stiffness by pulse wave velocity and augmentation index in 18 young healthy hookah smokers 21-39 years old, before and after ad lib 30-minute smoking/ inhalation session. To test for oxidative stress mediation, we will determine if any acute impairment in endothelial function after e-hookah can be prevented by intravenous Vitamin C infusion, a potent anti-oxidant. Antioxidant defensive buffers, such as protective HDL or paraoxonase-1 activity, or an increase in oxidized lipoproteins will be collected. To test for inflammatory mediation, biomarkers including anti-inflammatory cytokine IL-10 and pro-inflammatory cytokines hsCRP, TNF-?, IL-6, IL-8 will be collected before and after the sessions as well as smoking exposure biomarkers (plasma nicotine and expired CO). The results of this proposal stand to fill in gaps in our mechanistic understanding of the comparative effect of traditional vs. e-hookah bowl on vascular and endothelial function and in so doing, inform policy decisions by the FDA about regulation of hookah products.